Sinonasal Malignancies Involving the Frontal Sinus: A Mono-Institutional Experience of 84 Cases and Systematic Literature Review

Frontal sinus involvement by malignant tumors is a rare finding. Therefore, a systematic literature review along with a personal case series may contribute to defining more accurately the epidemiology, treatment options, and outcomes of these neoplasms. This is a retrospective review of patients affected by frontal sinus malignancies surgically treated in a tertiary-care referral center over a period of 20 years. Moreover, a systematic literature review of studies describing frontal sinus cancers from 2000 to date was performed according to PRISMA guidelines in order to analyze current evidence about the treatment and outcomes of such a rare disease. Our retrospective review was basedon 84 cases, treated with an exclusive endoscopic approach in 43 cases (51.2%), endoscopic approach with frontal osteoplastic flap in 6 cases (7.1%), and transfacial or transcranial approaches in 35 cases (41.7%). The five-year overall, disease-specific, disease-free, and recurrence-free survivals were 54.6%, 62.6%, 33.1%, and 59.1%, respectively. Age, dural involvement, type of surgical resection, and surgical margin status were significantly associated with the survival endpoints. In conclusion, the involvement of the frontal sinus is associated with a poor prognosis. Multidisciplinary management, including specific histology-driven treatments, represents the gold standard for improving outcomes and minimizing morbidity.


Introduction
Frontal sinus malignancies are uncommon, and they are usually the result of a direct extension of the tumor from the nasal cavity or anterior ethmoid sinuses into the frontal sinus [1]; conversely, malignancies directly arising from the sinus itself constitute an extremely rare finding [2].
The most frequent histologic types are represented by squamous cell carcinomas (SCC, 39.8%), mature B-cell lymphomas (17.5%), epithelial neoplasms not otherwise specified (10.5%), and adenocarcinomas (ADC, 9.9%) [3]. Finally, metastatic disease to the frontal sinus has been reported occasionally in the literature, and, in these cases, the most common primaries are represented by kidney, breast, lung, and gastrointestinal tract tumors [4].
Overall, frontal sinus malignancies show a very poor prognosis, with a 5-year diseasespecific survival (DSS) of 44.2% regardless of the histology [1]. Several reasons account for such dismal outcomes, including late diagnosis due to non-specific symptoms, the biology of the disease [5], and the early propensity of tumors involving this area to easily invade In detail, surgery was performed in the case of well-differentiated tumors and poorlydifferentiated tumors non-responders to induction chemotherapy. For the evaluation of the response rate to induction chemotherapy, the RECIST 1.1 criteria have been followed [9]. The definition of responders versus non-responders as well as indications for subsequent treatment planning have been described in a previous publication [10]. Regarding the skull base reconstructive plan after surgical resection, local endonasal flaps (e.g., nasoseptal or anterior ethmoidal arteries' septal flaps) were used whenever feasible and if not involved by cancer. The pericranial flap was harvested in the case of transcranial approaches, whilst pedicled free flaps were generally employed after transfacial resections.
All cases were re-classified according to the 8th edition of the "TNM classification of malignant tumors" for sinonasal cancer [11]. All neoplasms were classified according to the 4th edition of the "WHO classification of Head and Neck tumors" [12]. Written informed consent was obtained from each participant/patient for study participation and data publication. The study was approved by the Institutional Review Board (Insubria Board of Ethics, approval number 0033025/2015). All study procedures were performed in accordance with the 1964 World Medical Association's Declaration of Helsinki and its later amendments or comparable ethical standards.

Statistical Analysis
The main endpoints analyzed were overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS), and recurrence-free survival (RFS). OS was defined as the time from surgery to the last follow-up or death from any cause. DSS was defined as the time interval between surgery and death from disease. DFS was defined as the time from surgery to the first relapse at any site or death from any cause. RFS was defined as the time from surgery until relapse (either local, regional, or distant). Survival probability was assessed using the Kaplan-Meier survival analysis and the log-rank test was performed to compare survivals. Age (i.e., ≤60 years vs. >60 years), presentation (i.e., naive vs. relapses), histology, pT classification (i.e., pT3 vs. pT4a-4b), tumor epicenter (i.e., frontal vs. others), dural involvement (i.e., yes vs. no), type of surgery (i.e., exclusive endoscopic vs. combined vs. external approaches), surgical margins (i.e., R0 vs. R+), grading (i.e., G1-2 vs. G3), and adjuvant treatment (i.e., yes vs. no) were tested as prognostic factors.
A multivariate proportional hazard Cox regression was used for the same endpoints (OS, DSS, DFS, and RFS) considering variables significant in univariate analysis and/or with relevant clinical value. The results are presented in terms of hazard ratios (HR), 95% confidence intervals (CIs), and p-values. All statistical tests were two-tailed and statistical significance was considered when p-value ≤ 0.05. IBM SPSS software ® , version 25 (Chicago, IL, USA), was used to perform all statistical analyses.
The total recurrence rate was 39.3% (33/84 patients, Table 2) and half of the patients experienced early recurrences, within 9 months. Local failure was the most frequent event in 19/33 cases (57.6%), while dissemination of disease was observed in 13/33 cases (39.4%): multi-organ (7 cases), brain (3 cases), liver (1 case), and bones (2 cases). Treatment of recurrences was surgically-based in 7/33 cases (21.2%), non-surgical (RT and/or CRT) in 19/33 cases (57.6%), and 7/33 (21.2%) patients were addressed to best supportive care. Age was confirmed to be an independent prognostic factor in terms of OS and DSS in multivariate analysis ( Table 4). The type of surgical resection was associated with prognosis since patients affected by locally advanced cancers who required more extensive procedures (e.g., transcranial approaches) were more prone to recurrences (HR 3.3 in RFS, p = 0.006), while the status of surgical margins was associated with a close-to-significance increased risk of death and recurrence (HR 1.7 in DFS, p = 0.062).

Discussion
Frontal sinus malignancies are rare, comprising less than 2% of all cases of sinonasal malignancy [57], and include both tumors arising from the sinus itself and those extending into it from adjacent anatomical areas [3]. Therefore, the literature on studies focusing on malignancies involving this specific anatomical region is scarce and it is mainly represented by single case reports, with wide heterogeneity in histologies and treatment strategies. The work by Bhojwani et al. [1] reports 171 cases of malignancies involving the frontal sinus treated from 1973 to 2012 and represents the largest reported cohort currently available in the literature. Being a database-based study, it collects data derived from different institutions and it considers a broad period of time, for the most part before the introduction of recent advances in multimodal treatment strategies [58]. All this should be taken into consideration when drawing conclusions for clinical practice. Nonetheless, Bhojwani et al. report that frontal sinus malignancies are characterized by a very unfortunate prognosis, with a five-year DSS of 44.2% [1]. The present literature review seems to confirm this trend, considering that the pooled five-year DSS of all the included case reports was 67% after excluding lymphatic tumors, which are managed with (chemo)radiation and often characterized by better prognosis. Epithelium-derived cancers, on the contrary, are advanced by definition and pose challenges for both diagnosis and treatment, which significantly impacts prognosis. Common manifestations include swelling of the forehead, frontal headache, and indirect signs of orbital invasions, such as diplopia and proptosis [59]. Unfortunately, the symptoms are generally associated with an extension of the disease beyond frontal sinus boundaries, with the involvement of adjacent areas such as the orbit or the intracranial compartment, which is not infrequent at the time of diagnosis [2].
In light of the fact that frontal sinus cancers are rare, this sinus is not considered a "primary site" in the staging system promoted by the American Joint Committee on Cancer (AJCC) [60] and the Union for International Cancer Control (UICC) [11]: these organizations, in fact, primarily mentioned the nasal cavity, maxillary, and ethmoid sinuses and consider the frontal sinus only in the cases of secondary involvement (stage T4a). In 2002, the University of Florida grouped patients with frontal sinus malignancies into three stages: stage I, if limited to the site of origin; stage II, if the tumor extends to adjacent sites (i.e., orbit, nasopharynx, paranasal sinuses, skin, and pterygomaxillary fossa); and stage III, in the case of skull base, pterygoid plate, or intracranial involvement [61].
Diagnosis is made on imaging studies such as computed tomography (CT) and magnetic resonance (MR), which should precede biopsy, which is mainly performed via a minimally invasive approach (i.e., endoscopic transnasal approach), in order to define the histological profile of the cancer before planning the definitive treatment. This should be recommended in clinical practice since nowadays histotype has proven to be one of the main determinants of prognosis and essential to establishing the most appropriate multidisciplinary treatment strategy [5,7,8]. In this regard, the slightly better oncologic outcomes observed in the present cohort, compared to the observation by Bhojwani et al. [1], with a five-year DSS of 62.6%, might be in part explained by the implementation of histologydriven multimodal strategies in the management of such cancers, especially in locallyadvanced and poorly-differentiated neoplasms (Figure 3). In the present case series, the most common histotype was SCC (25%), in line with the literature [1,2], followed by aggressive entities such as MM (16.7%), SNEC, and SNUC (15.5%). The last three were much more common than what was observed in the systematic literature review (MM, 3.9%, and neuroectodermal tumors, 9.8%). Indeed in the database analysis by Bhojwani et al. [1] melanomas and neuroepitheliomatous neoplasms accounted for less than 6% of all frontal sinus malignancies. In one large recently published series on endoscopically treated sinonasal malignant tumors [7], the percentages of MM and SNEC/SNUC were 7.6-9.6% and 6.1-8.6% respectively, thus stressing the difference in histotype distribution between "primary sites" (ethmoid, nasal cavity, and maxillary sinus) and frontal sinus cancers, in which undifferentiated and aggressive histotypes are significantly represented, as shown by the present study.
Among rhinologists, the frontal sinus is recognized to be one the most challenging areas to reach surgically and, even nowadays, external approaches might be needed to manage specific situations (Figure 4) [62]. Over the years, instrumental and technological evolutions have allowed the application of minimally-invasive endoscopic approaches in the management of frontal disease, even in the case of malignant tumors. Currently, endoscopic transnasal and external approaches (i.e., transcranial/transfacial) should be considered as complementary techniques that must be mastered by the skull base surgeon, who must be able to switch from endonasal to external procedures whenever required, depending on intraoperative findings ( Figure 5). Flowchart of the study protocol, describing the multimodal treatment algorithm for the management of the malignancies involving the frontal sinus. The response rate to induction chemotherapy was defined according to the RECIST 1.1 criteria [9]. Abbreviations: ACC, adenoid cystic carcinoma; ADC, adenocarcinoma; BSC, best supportive care; CER, cranio-endoscopic resection; CFR, craniofacial resection; CHT, chemotherapy; EER, endoscopic endonasal resection; ERTC, endoscopic resection via transnasal craniectomy; FS, frontal sinus; iCHT, induction chemotherapy; ITAC, intestinal-type adenocarcinoma; OPF, osteoplastic flap; RT, radiotherapy; SCC, squamous cell carcinoma; SNEC, sinonasal neuroendocrine carcinoma; SNUC, sinonasal undifferentiated carcinoma. Undoubtedly, the goal of surgery is to achieve a free-margin resection, as the status of surgical margins has proven to be a transversal negative prognosticator among sinonasal malignancies [8], strictly linked with the high rate of relapses. The oncological concept of free-margin resection was supported also by our cohort, in which infiltrated surgical margins were associated with a significantly increased hazard ratio (HR) in 5-year DFS on multivariate analysis (p = 0.062).
The present study has some limitations that cannot be neglected. Firstly, it is based on a retrospective analysis of cases over a 20-year period, which might have introduced biases related to changes in staging systems and treatment modalities. Second, the wide heterogeneity of histologies within the broad panorama of sinonasal malignancies forced us to use a simplistic stratification in a few groups. Third, our systematic literature review is mainly represented by single case reports, hence with low scientific evidence, and heterogeneity in histotypes and treatment strategies. It should be mentioned that there might be larger studies in the literature focusing on sinonasal malignancies, with some reported cases of frontal sinus involvement. However, it was not possible to extrapolate from these studies individual data of patients with frontal sinus involvement adequate for the present analysis and therefore they were excluded from this systematic literature review.
Considering all these study limitations and open issues, it appears clear that the frontal sinus still represents a critical area in the management of sinonasal malignancies, with difficulties that have not been completely overcome. Future efforts should be devoted to focusing on prevention and early diagnosis as well as refining the multimodal histologydriven treatment strategies, which in the future will be tailored to the specific genetic and molecular assets of each patient, limiting external destructive surgical approaches to properly selected cases.

Conclusions
Malignant tumors involving the frontal sinus are rare and typically present as a secondary involvement of ethmoidal malignancies. Given the proximity to adjacent noble structures, such as anterior cranial fossa and orbit, they are usually diagnosed in advanced stages and associated with poor prognosis. Factors significantly associated with the survival endpoints were age, dural involvement, type of surgical resection, surgical margin status, and histology. Hence, nowadays, multimodal treatment protocols should be histology-based and patient-tailored, in order to maximize the chances of cure and minimize patient morbidity.